The present invention relates to steroid compounds substituted in position 11, the method of preparation, their application as medicine and pharmaceutical compositions containing them.
Osteoporosis is a pathology that is characterized by a quantitative and qualitative reduction of bane tissue, sufficient to lead to vertebral or peripheral fractures, occurring spontaneously or as a result of minimal trauma. Although this disorder is of multifactorial origin, in women the menopause is the predominant factor in bone loss or osteopenia.
This osteopenia is manifested by rarefaction and alteration of the architecture of the spongy bone which leads to increased fragility of the skeleton and increase in the risk of fractures. Bone loss increases considerably after the menopause owing to the decline in ovarian function and reaches 3 to 5% per year, but then slows down after the age of 65 years.
With a view to therapy, the hormone deficiency after the menopause can be compensated by hormone replacement therapy, in which oestrogen plays a major role by preserving bone mass. In the long term, however, oestrogen therapy is sometimes accompanied by undesirable effects on the genital system (endometrial hyperplasia, mammary tumours etc.), which constitutes a major drawback and limits its application.
It is therefore necessary to find compounds other than oestradiol that possess dissociated oestrogen activity, i.e. oestrogen activity in the bone tissue, yet with little or no activity of endometrial hyperplasia, nor activity of proliferation of mammary tumours.
The invention therefore relates to compounds of general formula (I): 
in which:
n is an integer equal to 2 or 3,
either R1 and R2, which may be identical or different, represent a hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms,
or R1 and R2 form, together with the nitrogen atom to which they are bound, a heterocycle, mono or polycyclic, saturated or unsaturated, of 5 to 15 units, aromatic or non-aromatic, optionally containing from 1 to 3 additional heteroatoms selected from oxygen, sulphur and nitrogen, substituted or unsubstituted,
X represents a hydroxyl radical, optionally esterified, and
Y represents an alkyl radical containing from 1 to 4 carbon atoms, as well as their pharmaceutically acceptable salts of addition with acids.
Alkyl radical containing from 1 to 4 carbon atoms is taken to mean methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl and tert-butyl radicals.
When R1 and R2 form, together with the nitrogen atom to which they are bound, a heterocycle, this means in particular saturated mono or bicyclic heterocycles optionally containing another heteroatom selected from oxygen and nitrogen, such as heterocycles selected from:
pyrrolyl, imidazolyl, indolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, oxazolyl, furazonyl, pyrazolinyl, thiazolinyl, and quite particularly the following saturated heterocycles: 
When this heterocycle is substituted, it is substituted in particular by an alkyl group containing from 1to 4 carbon atoms on the nitrogen atom.
When X is a hydroxyl radical, optionally esterified, we mean the OCO-alc1 groups in which alc1 is an alkyl radical containing from 1to 8 carbon atoms and preferably the groups xe2x80x94OCOMe and OCOEt.
By pharmaceutically acceptable salts of addition with acids, we mean salts of addition formed with inorganic or organic acids on the amine. Possible acids are hydrochloric, hydrobromic, nitric, sulphuric, phosphoric, acetic, formic, propionic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, alkanesulphonic such as methane- or ethane-sulphonic acids, arylsulphonic acids, such as benzene- or paratoluene-sulphonic acids and arylcarboxylic acids.
The invention relates more particularly to the compounds of formula (I) as defined above in which n is equal to 2, as well as their pharmaceutically acceptable salts of addition with acids.
The invention relates more particularly to the compounds of formula (I) as defined above in which:
n is equal to 2,
either R1 and R2, which may be identical or different, represent an alkyl radical containing from 1 to 4 carbon atoms,
or R1 and R2 form, together with the nitrogen atom to which they are bound, a piperidino, pyrrolidino or 2-azabicyclo(2.2.1)hept-2-yl group,
X represents a hydroxyl radical and Y represents a methyl or ethyl radical.
The invention relates quite particularly to compounds of formula (I) as well as their pharmaceutically acceptable salts of addition with acids, with the following names:
11xcex2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-19-nor-17xcex1-pregna-1,3,5(10)-triene-3,17xcex2-diol,
17xcex1-methyl-11xcex2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-oestra-1,3,5(10)-triene-3,17xcex2-diol,
17xcex1-methyl-11xcex2-[4-[2-(diethylamino)ethoxy]phenyl]-oestra-1,3,5(10)-3,17xcex2-diol,
17xcex1-methyl-11xcex2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-oestra-1,3,5(10)-triene-3,17xcex2-diol,
17xcex1-methyl-11xcex2-[4-[2-(2-aza-bicyclo(2.2.1)hept-2-yl)ethoxy]phenyl]-oestra-1,3,5(10)-triene-3,17xcex2-diol,
11xcex2-[4-[2-(2-aza-bicyclo(2.2.1)hept-2-yl) ethoxy]phenyl]-19-nor-17xcex1-pregna-1,3,5(10)-triene-3,17xcex2-diol,
17xcex1-(trifluoromethyl) 11xcex2-[4-[2-(1-piperidinyl)ethoxy]phenyl]oestra-1,3,5(10)-triene-3,17xcex2-diol.
The invention also relates to a method of preparation of the compounds of general formula (I) as defined previously, characterized in that a compound of general formula (II): 
in which n, R1 and R2 are as defined previously, is submitted to the action of an organometallic compound containing from 1 to 4 carbon atoms so as to form the compounds of formula (I) in which X is a hydroxyl group and Y is an alkyl group containing from 1 to 4 carbon atoms, and this compound of formula (I) is submitted if necessary to a reaction of esterification of the 17-OH and/or to a reaction of salification.
The action of an organometallic on the 17-keto group provides access to products of formula (1) in which X is a hydroxyl group and Y is an alkyl croup containing from 1 to 4 carbon atoms.
The organometallic compound derived from an alkyl radical containing from 1 to 4 carbon atoms is selected from among the magnesium compounds of formula Yxe2x80x94MgHal and the lithium compounds of formula Yxe2x80x94Li in which Y is as defined previously and Hal represents a halogen atom. Preferably the reaction takes place in the presence of cerium chloride. In a preferred manner of carrying out the method, Hal represents an atom of chlorine, bromine or iodine, preferably bromine.
To obtain compounds of formula (I) in which X is an hydroxyl radical and Ya CF3 group, the reaction is effected by the action of CF3SiMe3 on the 17-keto followed by the action of a deprotection agent such as tetrabutylammonium flouride.
The invention also relates to a method of preparation of compounds of general formula (I) as defined previously, with Y representing an alkyl radical containing from 2 to 4 carbon atoms, characterized in that a compound of general formula (III): 
in which n, R1 and R2 are as defined previously and in which y represents an alkenyl or alkynyl group containing from 2 to 4 carbon atoms, is submitted to the action of a reducing agent of the double bond or of the triple bond, so as to obtain compounds of formula (I) in which X is a hydroxyl group and Y is an alkyl group containing from 1 to 4 carbon atoms, this compound of formula (I) being submitted if necessary to a reaction of esterification of the 17-OH and/or to a reaction of salification.
The reaction of complete reduction can be carried out by the action of hydrogen in the presence of a catalyst such as palladium on carbon or a rhodium catalyst such as Wilkinson""s reagent.
The reactions of esterification and salification are carried out by the usual methods known by a person skilled in the art.
The compounds of general formula (I) as well as their pharmaceutically acceptable salts of addition with acids possess oestrogen activity, anti-oestrogen activity and anti-proliferative activity.
On this basis, the compounds of formula (I) can be used, in the treatment of disorders connected with hypofolliculinism, for example amenorrhoea, dysmenorrhoea, repeated miscarriages, premenstrual disorders, in the treatment of certain oestrogen-dependent pathologies such as adenomas or carcinomas of the prostate, carcinomas of the breast and their metastases or in the treatment of benign breast tumours, as anti-uterotrophic as well as in replacement therapy of the menopause or perimenopause.
The symptoms and consequences connected with the menopause are, more precisely: hot flushes, sweating, atrophy and dryness of the vagina, urinary symptoms and in the long term decrease in bone mass and increased risk of fracture, as well as the loss of cardiovascular protection afforded by the oestrogens.
In particular, the compounds of formula (I) as well as their pharmaceutically acceptable salts of addition with acids, can thus be used in the prevention or treatment of osteoporosis.
The compounds of formula (I) as well as their pharmaceutically acceptable salts of addition with acids can also be used in the prevention or treatment of osteoporosis in humans.
They can also be used in the prevention or treatment of secondary osteoporosis (for example cortisone-related osteoporosis, associated with immobilization).
The compounds of formula (I) as well as their pharmaceutically acceptable salts of addition with acids possess, in particular, a dissociated oestrogen activity.
Dissociated oestrogen activity means oestrogen activity in the bone which only exhibits minimal activity in the uterus, and so does not lead to endometrial proliferation (activity well below that of oestradiol).
Furthermore, the compounds according to the invention offer the following advantages:
They exhibit anti-oestrogen activity in the breast. In contrast to oestradiol, they do not stimulate the growth of human mammary tumour cells and can even inhibit their growth. The compounds according to the invention are therefore particularly advantageous for the treatment of the menopause in women at risk from breast cancer (family history) who are therefore excluded from replacement therapy with cestradiol. They can also be used in the treatment of breast cancers.
They lead to a lowering of the serum cholesterol level to a level equivalent to that induced by cestradiol. They thus reinforce cardiovascular protection.
Finally, the compounds according to the invention do not exhibit oestrogen activity in the uterus and so do not require to be administered in conjunction with a progestomimetic compound.
The invention therefore relates to compounds of general formula (I), as well as their pharmaceutically acceptable salts of addition with acids, as medicines.
The invention relates more particularly to the compounds of formula (I) as well as their pharmaceutically acceptable salts of addition with acids, as medicines for the prevention or treatment of osteoporosis.
The invention relates quite particularly to the compounds or general formula (I), as well as their pharmaceutically acceptable salts of addition with acids, as medicine intended for the prevention or treatment of osteoporosis, which exhibit little or no oestrogen activity on the uterus.
Finally the invention relates quite particularly to the compounds of general formula (I), as well as their pharmaceutically acceptable salts of addition with acids, as medicine intended for the prevention or treatment of osteoporosis in women at risk from mammary tumours.
The invention covers pharmaceutical compositions containing as active principle at least one of the medicines as defined above.
The compounds of formula (I) as well as their pharmaceutically acceptable salts of addition with acids, are administered via the alimentary canal, or parenterally or locally, for example percutaneously. They can be prescribed in the form of plain or coated tablets, capsules, granules, suppositories, pessaries, injectable preparations, ointments, creams, gels, microspheres, implants, intravaginal rings, patches, sprays, which are prepared by the usual methods.
The active principle or principles can be incorporated in them with the excipients usually employed in these pharmaceutical compositions, such as talc, cum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, the various wetting, dispersing or emulsifying agents, and preservatives.
The posology required varies according to the disorder to be treated and the route of administration; for example it can vary from 0.5 to 100 mg per day for an adult when taken orally.
The compounds of general formula (II) and (III) are known compounds that are described in the following patents: EP-B-0097572, FR-B-2640977, EP-B-305942.
The examples given below illustrate the invention though without limiting it.